Everything about Sean Parker’s first-in-human cancer trial of CRISPR gene editing technology is monumental, including ethical concerns about the safety of the first patients who will serve as true pioneers to test the potentially breakthrough cancer immunotherapy.
Financial conflicts of interest, questionable informed consent procedures and the variable of a celebrity billionaire’s eagerness to push forward a new therapy all suggest caution.
Last year, Parker, the 36-year-old Napster founder and first president of Facebook, established a $600 million foundation and this April assembled his “dream team” of U.S. cancer immunotherapy experts with promises of a $250 million contribution to six U.S. academic medical centers.
The medical centers, all world renowned, will work under the umbrella of the Parker Institute of Cancer Immunotherapy. Three institutes – led by the University of Pennsylvania (Penn) and including M.D. Anderson Center and University of California at San Francisco – will have a first crack out of the box with Parker’s money.
The funding will be used to conduct a phase I trial of CRISPR to edit genes of T cells, withdrawn from patients and reinfused after alteration, for attacking three kinds of cancer. The study will enroll 18 seriously ill adult melanoma, myeloma and sarcoma patients, whose disease has not responded to existing therapies.
The first-of-its kind clinical trial received a positive recommendation June 21 from the Recombinant DNA Advisory Committee (RAC) of the NIH. Before patients are enrolled the protocol still must be approved by the medical centers and the FDA.
Genome editing technology has raised a whole host of ethical issues, mostly involving application to human germ line cells. (See BioWorld Today, Feb. 2, 2016, and Feb. 16, 2016.)
Application to somatic cells, such as T cells, for immunotherapy is considered akin to gene therapy and not as controversial. Still ethical concerns in the Penn-led trial, some of which were raised by RAC members, can impact the success of the research, which emerged only four years ago. (See BioWorld Today, July 1, 2013.)
LEAP-FROGGING TRADITIONAL STRATEFIES
First there is the question of whether the therapy is moving too quickly, championed by a private donor leap-frogging over traditional funding strategies represented by emerging companies such as Editas Medicines Inc., of Cambridge, Mass. (See BioWorld Today, Nov. 25, 2013.)
That’s a legitimate question,” agreed Otis Brawley, chief medical officer of the American Cancer Society. “My impression is that the people using this technology are being very careful.”
The sentiment mirrors RAC’s, expressed by bioethicist Laurie Zoloth, of Northwestern University. She told BioWorld Today she relied on the expertise of Penn researchers, led by immunotherapy professor Carl June, in deciding the trial should be attempted.
Brawley, who praised Parker for his efforts, said medical researchers are looking for alternatives to government and industry funding for early stage clinical development, and philanthropy is a legitimate source.
As for a private donor potentially hijacking resources to push a personal agenda, Brawley said, “That’s part of my responsibility, making sure the entire research agenda is not diverted to one area. We need to look at prevention and treatment, and within treatment we need to look at everything.”
Within the cancer research community, Brawley added, immunotherapy was ignored for years. “What I’m saying is, we failed” to recognize its potential, he suggested.
WHO OWNS IT AND WHO BENEFITS?
With Parker’s funding model comes significant questions about potential financial conflicts of interest. Who will own intellectual property (IP) derived from clinical trials and who will benefit from it?
The Parker Institute of Cancer Immunotherapy’s legal counsel, Melanie Griffith, told BioWorld Today, the institute will hold administrative rights for the IP.
“Our specialists,” Griffith said, “will work closely with our partners to ensure robust patent protections of all new discoveries and will pursue investments, licenses, sales, spin-offs and other strategies to help develop and monetize each new technology, from preclinical through later stage development.”
How will this approach affect the medical centers as well as the eventual patient access to a marketed therapy?
If the technology yields the kind of revolutionary breakthrough expected, prices likely will be higher than the previous generation of cancer immunotherapies, such as Provenge (sipuleucel-T), which cost $93,000 for a single course of treatment. (See BioWorld Today, Nov. 19, 2010.)
“My hope,” Brawley said, “is that philanthropies [in general] don’t try to monetize their intellectual property into expensive treatments patients can’t afford.”
There’s also the question of the impact on the participating medical centers. How cautious will they act in partnership with a generous benefactor whose investments go far beyond a single study and have the potential to bring them wealth and prestige? It’s a question also asked when industry gets close to academia.
Then there is a more specific financial conflict involving the University of Pennsylvania and June, one of the world’s leading cancer immunotherapy experts and the owner of patents on IP related to CRISPR technology. June acknowledged to RAC members June 21 that he has a significant financial conflict.
RAC bioethicist Lainie Ross, of the University of Chicago, suggested the conflict was worrisome enough to exclude Penn from participating in the phase I trial. She even raised the specter of Jesse Gelsinger, a gene therapy patient who died in a clinical trial led by a Penn investigator with the financial conflict of interest. (See BioWorld Today, Dec. 10, 1999.)
“Penn does have an infamous history in this regard,” said Ross, who nevertheless voted in favor of the trial protocol with Penn involved.
WILL PATIENTS REALLY UNDERSTAND?
Beyond the financial conflicts, is the serious issue of insuring the informed consent of patients participating in the trial. Voluntary informed consent is the cornerstone of ethical clinical research. Key elements involve detailing potential side effects and dispelling any therapeutic misconception that desperate patients will directly benefit from experimental therapy.
RAC members reviewed Penn’s proposed informed consent documents. They recommended significant changes emphasizing that patients were unlikely to benefit, detailing Penn’s financial conflicts and stressing the first-of-its kind significance of the study, essentially identifying the patients as medical pioneers.
When it comes to potential side effects investigators likely will face significant challenges in trying to explain to patients the complicated science of the potential for off-target genome editing and the impact of having millions of altered T cells circulating through their bodies for an indefinite amount of time.
Without fully understanding the risks and lack of benefits, eager pioneers cannot give informed consent.
In addition Parker said during a Forbes panel session, broadcast online in early June, that a central institutional review board (IRB) will be used by all six medical centers to approve Parker-funded clinical trials, presumably eliminating local IRB control and further fast-tracking the research.
During the same Forbes broadcast, June extolled the virtues of his benefactor. “To do this [phase I trial] through standard funding mechanisms would either be impossible or take too long,” he said. Parker, he observed, has “the vision to do what is not possible.”
RAC recommendations are not binding. The difficult details of the phase I trial will be sorted out by the FDA. However, in the long run, the relationship between the medical centers and their benefactor may be as important as any other factor for cancer patients.
Charles Craig is a writer, editor and lecturer on bioethics and biotechnology issues with a master of arts in bioethics and master of journalism degree. He has more than 20 years of experience in the biotech industry as the former president of Georgia Bio, author and editor of Ernst & Young’s annual Global Biotechnology Report (2001-05), director of publications with the Biotechnology Innovation Organization (1998-2001) and writer and editor with BioWorld Today (1994-98).
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The views expressed in this column are solely those of the author and do not reflect the views of BioWorld Today or Thomson Reuters.